Arylalkyl (thio) amides

ABSTRACT

A compound which is selected from those of formula (I):   &lt;IMAGE&gt; (I) in which A, R1, R2, R3, R4, R5 and R6 are as defined in the description, its optical isomers, and its addition salts thereof with a pharmaceutically-acceptable acid or base, and medicinal products containing the same which are useful for treating a disorder of the melatoninergic system.

The present application is a continuation of our prior-filed applicationSer. No. 08/131,207, filed Oct. 1, 1993, now abandoned.

The application relates to new arylalkyl(thio)amides, to a process forpreparing them and to pharmaceutical compositions containing them.

Application EP 238,868 has already described compounds ofphenylalkylamide structure, presenting them as tyrosine kinaseinhibitors and antitumor and antibacterial agents.

Many studies have demonstrated the major role of melatonin(5-methoxy-N-acetyltryptamine) in the control of the circadian rhythmand the endocrine functions, and the melatonin receptors have beencharacterized and localized. The practitioner hence has a real need forcompounds that have an action on the melatoninergic system.

The Applicant discovered that new compounds of arylalkyl(thio)amidestructure, substituted on their benzene ring with a hydroxyl or alkoxyradical specifically at the ortho position with respect to thealkyl(thio)amide chain, possessed very considerable activity withrespect to the melatoninergic system, whereas these properties are notencountered with compounds substituted at the meta or para position withrespect to the alkyl(thio)amide chain.

More especially, the present invention relates to the compounds offormula (I): ##STR2## in which: A represents a --CH₂ --CH₂ -- chain,unsubstituted or substituted with a lower alkyl,

R₁ represents a hydrogen atom or a lower alkyl,

R₂ represents a hydrogen atom, a halogen atom or a lower alkyl,

R₃ and R₄, which may be identical or different, each represent,independently of one another, a radical chosen from:

hydrogen,

halogen,

lower alkyl,

cyano,

carboxyl,

nitro,

amino,

lower alkylamino,

lower dialkylamino,

--(CH₂)_(n) --E₁ in which n represents 0 or an integer from 1 to 4, andE₁ represents a cycloalkyl or a cycloalkenyl and contains from 3 to 8carbon atoms, E₁ being unsubstituted or substituted with one or moreradicals chosen from halogen, oxo and lower alkyl,

and --(CH₂)_(n') --E₂ in which n' represents 0 or an integer from 1 to 4and E₂ represents a radical chosen from: phenyl, naphthyl, pyrrolyl,thienyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyland isoquinolyl, E₂ being unsubstituted or substituted with one or moreradicals chosen from: halogen, hydroxyl, lower alkyl, lower alkoxy andtrifluoromethyl,

or R₃ and R₄, together with the benzene ring which carries them, form aring-system E₃ chosen from: indene, naphthalene, benzothiophene,benzofuran, indole, benzimidazole, benzopyran, benzothiopyran,quinoline, isoquinoline, indazole, quinoxaline, quinazoline, cinnoline,benzothiazole, benzothiazole, benzoxazole, benzisoxazole, benzoxazine,benzothiazine, benzodioxole and benzodioxane, on the understanding thatthe portion of the ring-system E₃ formed by R₃ and R₄ and the two carbonatoms of the benzene ring which carry them is:

unhydrogenated or partially hydrogenated,

and unsubstituted or substituted with one or more radicals chosen from:halogen, hydroxyl, lower alkyl, lower alkoxy, lower alkoxycarbonyl andtrifluoromethyl,

R₅ represents a hydrogen atom or a lower alkyl,

R₆ represents a group ##STR3## in which X represents a sulfur or oxygenatom and R₇ represents a radical chosen from:

lower alkyl, unsubstituted or substituted with one or more radicalschosen from halogen, hydroxyl and lower alkoxy,

linear or branched alkenyl having 2 to 7 carbon atoms, unsubstituted orsubstituted with one or more radicals chosen from halogen, hydroxyl andlower alkoxy,

and --(CH₂)_(m) --E₄ in which m represents 0 or an integer from 1 to 4and E₄ represents a mono- or bicyclic cycloalkyl having 3 to 12 carbonatoms, unsubstituted or substituted with one or more radicals chosenfrom halogen, oxo and lower alkyl,

with the proviso that R₇ can represent a lower alkyl, unsubstituted orsubstituted with one or more radicals chosen from halogen, hydroxyl andlower alkoxy, only if R₃ and R₄ form a ring-system E₃ as defined abovewith the benzene ring which carries them, or if one of the substituentsR₃ and R₄ represents a lower alkyl and the other substituent R₃ or R₄represents a hydrogen atom, their optical isomers, and their additionsalts with a pharmaceutically acceptable acid or base when R₃ or R₄represents a salifiable group, on the understanding that the terms"lower alkyl" and "lower alkoxy" denote linear or branched groups having1 to 6 carbon atoms and that the terms "cycloalkenyl" and "alkenyl"denote hydrocarbon groups containing one or more double bonds.

The invention also encompasses:

the compounds according to the formula (I) in which R₃ and R₄, togetherwith the benzene ring which carries them, form a ring-system E₃ chosenfrom: indene, naphthalene, benzothiophene, benzofuran, indole,benzimidazole, benzopyran, benzothiopyran, quinoline, isoquinoline,indazole, quinoxaline, quinazoline, cinnoline, benzothiazole,benzisothiazole, benzoxazole, benzisoxazole, benzoxazine, benzothiazine,benzodioxole and benzodioxane, on the understanding that the portion ofthe ring-system E₃ formed by R₃ and R₄ and the 2 carbon atoms of thebenzene ring which carry them is:

unhydrogenated or partially hydrogenated,

and unsubstituted or substituted with one or more radicals chosen from:halogen, hydroxyl, lower alkyl, lower alkoxy, lower alkoxycarbonyl andtrifluoromethyl,

the compounds according to the formula (I) in which R₃ and R₄, togetherwith the benzene ring which carries them, form a naphthalene, on theunderstanding that the benzene ring formed by R₃, R₄ and the 2 carbonatoms which carry them is unsubstituted or substituted with one or moreradicals chosen from halogen, hydroxyl, lower alkyl, lower alkoxy, loweralkoxycarbonyl and trifluoromethyl,

and the compounds according to the formula (I) in which R₁ represents amethyl radical and R₃ and R₄, together with the benzene ring whichcarries them, form a naphthalene, on the understanding that the benzenering formed by R₃ and R₄ and the 2 carbon atoms which carry them isunsubstituted or substituted with one or more radicals chosen from:halogen, hydroxyl, lower alkyl, lower alkoxy, lower alkoxycarbonyl andtrifluoromethyl.

Among pharmaceutically acceptable acids which may be used to form anaddition salt with the compounds of the invention, hydrochloric,sulfuric, phosphoric, tartaric, malic, maleic, fumaric, oxalic,methanesulfonic, ethanesulfonic, camphoric and citric acids may bementioned as examples and without implied limitation.

Among pharmaceutically acceptable bases which may be used to salify thecompounds used according to the invention, sodium hydroxide, potassiumhydroxide, triethylamine, diethylamine, ethanolamine, arginine, lysineand diethanolamine may be mentioned as examples and without impliedlimitation.

The invention also encompasses the process for preparing the compoundsof formula (I), wherein: a compound of formula (II): ##STR4## in whichA, R₁, R₂, R₃, R₄ and R₅ are as defined in the formula (I), is reactedwith a compound of formula (III): ##STR5## or of formula (IV): ##STR6##in which formulae R₇ is as defined in the formula (I) and Hal representsa halogen atom, to obtain a compound of formula (I/a): ##STR7## in whichA, R₁, R₂, R₃, R₄, R₅ and R₇ are as defined above, which compound offormula (I/a) is subjected to Lawesson's reagent in order to obtain thecompound of formula (I/b): ##STR8## in which A, R₁, R₂, R₃, R₄, R₅ andR₇ are as defined above, the compounds of formulae (I/a) and (I/b)forming the set of compounds of formula (I), it being possible for thecompounds of formula (I) to be:

purified according to one or more purification methods chosen fromcrystallization, chromatography on a silica column, gas chromatography,extraction, filtration and passage through charcoal or resin,

separated, where appropriate, in pure form or in the form of a mixture,into their possible optical isomers,

or salified with a pharmaceutically acceptable acid or base.

The starting compounds used in the process for preparing the compoundsof formula (I) are:

either commercially available

or readily accessible to a person skilled in the art using processescontained in the literature.

The compounds of formula (II) are, in particular, readily accessible toa person skilled in the art, when A represents an ethylene moiety, byreducing a compound of formula (II/a): ##STR9## in which R₁, R₂, R₃ andR₄ are as defined in the formula (I), to obtain a compound of formula(II/b): ##STR10## in which R₁, R₂, R₃ and R₄ are as defined above, whichis then subjected to a halogenating agent to obtain a compound offormula (II/c): ##STR11## in which R₁, R₂, R₃ and R₄ are as definedabove and Hal' represents a halogen atom, which compound of formula(II/c) is reacted with potassium cyanide in order to obtain the compoundof formula (II/d): ##STR12## in which R₁, R₂, R₃ and R₄ are as definedabove, which gives, after hydrogenation, the compound of formula (II/e):##STR13## in which R₁, R₂, R₃ and R₄ are as defined above, whichcompound of formula (II/e) can be, where appropriate, reacted with acompound of formula (V):

    Hal"--R.sub.5'                                             (V)

in which R_(5') represents a linear or branched alkyl having 1 to 6carbon atoms and Hal" represents a halogen atom, to obtain the compoundof formula (II/e'): ##STR14## in which R₁, R₂, R₃, R₄ and R_(5') are asdefined above, the compounds of formulae (II/e) and (II/e') forming theset of compounds of formula (II), it being possible for the compounds offormula (II) to be:

purified according to one or more purification methods chosen fromcrystallization, chromatography on a silica column, gas chromatography,extraction, filtration and passage through charcoal or resin,

separated, where appropriate, in pure form or in the form of a mixture,into their possible optical isomers,

or salified with a pharmaceutically acceptable acid or base.

The compounds of formula (II/e) as defined above are also readilyaccessible to a person skilled in the art by reacting a compound offormula (II/a): ##STR15## in which R₁, R₂, R₃ and R₄ are as defined inthe formula (I), with nitromethane in order to obtain a compound offormula (II/f): ##STR16## in which R₁, R₂, R₃ and R₄ are as definedabove, which is then reduced to obtain the corresponding compound offormula (II/e).

The compounds of formula (II) in which A represents an ethylene moietysubstituted with a lower alkyl may be obtained by a person skilled inthe art by reacting a compound of formula (II/a): ##STR17## in which R₁,R₂, R₃ and R₄ are as defined in the formula (I), with a nitro compoundof formula (II/g):

    A'--NO.sub.2                                               (II/g)

in which A' represents a methyl group substituted with a lower alkyl, inorder to obtain a compound of formula (II/f'): ##STR18## in which R₁,R₂, R₃ and R₄ are as defined above and A" represents an ethylene moietysubstituted with a lower alkyl, which compound of formula (II/f') issubjected to a reduction step and, where appropriate, alkylated byreaction with a compound of formula (V):

    Hal'"--R.sub.5'                                            (V)

in which R_(5') represents a linear or branched alkyl having 1 to 6carbon atoms and Hal'" represents a halogen atom, in order to obtain thecorresponding compound of formula (II).

The Applicant discovered that the compounds of the invention possessednoteworthy activity with respect to the melatoninergic system. Theyexhibit, in particular, a very high affinity for melatonin receptors.

This very considerable binding capacity is demonstrated in Example B(study of binding to melatonin receptors) of the present application.

The intensity of this pharmacological property of the compounds of theinvention proved surprising, since it is not encountered with compoundsin which the hydroxyl or alkoxy group is a substituent at the meta orpara position of the benzene ring carrying the alkylamide chain.

By virtue of their action on melatonin receptors, the compounds of theinvention are hence new candidates for the treatment of disorders of themelatoninergic system.

Pathologies in which melatonin is involved are, in particular, sleepdisorders, depression, Parkinson's disease, Alzheimer's disease, cancer,jet lag, immune disorders, migraine, diabetes and stress. Melatonin isalso implicated in a mechanism of inhibition of ovulation.

The invention also encompasses pharmaceutical compositions containing asactive principle at least one of the compounds of formula (I) or one ofits addition salts with a pharmaceutically acceptable acid or base, incombination with one or more pharmaceutically acceptable excipients.

Among the compositions according to the invention, there may bementioned, as examples and without implying any limitation, those whichare suitable for oral, parenteral, ocular, per- or transcutaneous,nasal, rectal, perlingual or respiratory administration, and inparticular injections, aerosols, eye or nose drops, tablets, sublingualtablets, capsules including hard gelatin capsules, troches, preparationsto be held under the tongue, suppositories, creams, ointments and gels.

The preparations thereby obtained generally take the form of individualmeasured doses, and can contain, depending on the pathologies beingtreated and the patient's age and sex, from 0.01 to 100 mg in dosestaken from one to three times a day, and more especially from 0.1 to 100mg, for example from 0.1 to 10 mg.

The examples which follow illustrate the invention and in no way limitit. The structure of the compounds is verified by nuclear magneticresonance.

PREPARATION 1: 2-(2-METHOXY-1-NAPHTHYL)ETHYLAMINE

First method:

STAGE A: (2-METHOXY-1-NAPHTHYL)METHANOL

40 cm³ of anhydrous tetrahydrofuran (THF) are placed under argon in a250-cm³ two-necked flask. 3.1 g of lithium aluminum hydride are added. Asolution of 5 g of (2-methoxy-1-naphthyl)carbaldehyde in 30 cm³ ofanhydrous tetrahydrofuran is added to this mixture with stirring.Reaction is allowed to proceed at room temperature for 16 h. Hydrolysisis performed according to the following method:

3.1 cm³ of water are added to the mixture, which is left stirring for 5min,

3.1 cm³ of 15% sodium hydroxide solution are then added, and the mixtureis left stirring again for 5 minutes,

9.3 cm³ of water are then added until a whitish pasty mixture isobtained.

After incorporation of sodium sulfate and stirring for a further fewminutes, the mixture is filtered and the filtrate is concentrated in arotary evaporator.

White crystals of the desired alcohol, representing a mass of 4.87 g,are thereby obtained. (Yield: 96%).

The compound is recrystallized in the heated state in an isopropylether/ethanol mixture to give 3.65 g of white crystals of(2-methoxy-1-naphthyl)methanol.

Melting point: 100.9°±0.2° C.

¹ H NMR (CDCl₃, 200 MHz) 2.01 ppm (1H (OH), b.s.) 3.90 ppm (3H (CH₃ O),s.) 5.10 ppm (2H (CH₂ O), s.) 7.17-8.06 ppm (6H (aromatic), m.)

STAGE B: 1-CHLOROMETHYL-2-METHOXYNAPHTHALENE

2.21 g of the compound obtained in Stage A are placed in a 100-cm³two-necked flask. The flask is placed under argon. 17.6 cm³ of toluene(1.5 equivalents) are incorporated, followed by 0.94 cm³ of pyridine (1equivalent). The flask is immersed in an ice bath. A solution of 2 cm³of thionyl chloride in 12 cm³ of toluene is then added via apressure-equalizing dropping funnel. A white precipitate forms. Afterthe addition, the ice bath is removed. Reaction is allowed to proceed atroom temperature for 15 h.

This mixture is poured into ice; the reaction medium is left stirringfor 45 min. After separation of the aqueous and organic phases, thelatter is washed once with water, once with saturated sodium hydrogencarbonate solution and then once with saturated sodium chloridesolution. After drying over magnesium sulfate and concentration of thefiltrate, a yellow crystalline product of mass 2.24 g, corresponding to1-chloromethyl-2-methoxynaphthalene, is isolated. (Yield: 92.3%).

These crystals may be recrystallized in the heated state in ethyl ether;1-chloromethyl-2-methoxynaphthalene is a crystalline white solid.

Melting point : 122.7°±0.2° C.

¹ H NMR (CDCl₃, 200 MHz) 3.92 ppm (3H (OCH₃), s.) 5.10 ppm (2H (CH₂ Cl),s.) 7.18 ppm (1H (arom.), s. J=8.9 Hz) 7.27-7.34 ppm (1H (aromatic), m.)7.45-7.53 ppm (1H (aromatic), m.) 7.73 ppm (1H (aromatic), d. J=8.9 Hz)7.77 ppm (1H (aromatic), d. J=8.9 Hz) 7.96 ppm (1H (aromatic), d. J=8.9Hz)

STAGE C: 1-CYANOMETHYL-2-METHOXYNAPHTHALENE

The reaction involves 1.14 g of the compound obtained in Stage B, 0.718g of potassium cyanide (2 equivalents) and a small spatula of potassiumiodide, these reactants being present in 12 cm³ of anhydrous dimethylsulfoxide (2 equivalents). It is carried out under argon at 120°-140°C., and lasts 8 h. Treatment after the reaction yields rust-coloredcrystals, which are recrystallized in the heated state in a hexane/ethylacetate mixture.

0.665 g of beige crystals of 1-cyanomethyl-2-methoxynaphthalene isthereby isolated. (Yield: 61%).

Melting point: 95.4°±0.2° C.

¹ H NMR (CDCl₃, 200 MHz) 3.94 ppm (3H (CH₃ O), s.) 4.05 ppm (2H (CH₂CN), s.) 7.18-7.83 ppm (6H (aromatic), m.)

STAGE D: 2-(2-METHOXY-1-NAPHTHYL)ETHYLAMINE

The reaction is performed on 0.6 g of the compound obtained in thepreceding stage (3 mmol), in 10 cm³ of absolute ethanol (3 equivalents)and 1 cm³ of ammonium hydroxide.

The compound is hydrogenated at atmospheric pressure and at roomtemperature on Raney nickel. Reaction is allowed to proceed for 23hours. The catalyst is removed by filtration on a layer of Celite andrinsed with absolute ethanol. The filtrate is concentrated in a rotaryevaporator. The amine hydrochloride is then formed: the mixture isdiluted in methanol, methanolic hydrogen chloride is added and thehydrochloride is precipitated by adding isopropyl ether.

0.468 g of yellow crystals of 2-(2-methoxy-1-naphthyl)ethylaminehydrochloride is thereby isolated. (Yield: 64.5%)

Melting point: >180° C.

¹ H NMR (CD₃ OD, 200 MHz) 3.30-3.37 ppm (2H (CH₂ --), m.) 3.62-3.69 ppm(2H (CH₂ N), m.) 4.19 ppm (3H (CH₃ O), s.) 7.55-7.76 ppm (3H (aromatic),m.) 8.01-8.20 ppm (3H (aromatic), m.)

Second method:

STAGE A': 1-NITRO-2-(2-METHOXY-1-NAPHTHYL)ETHYLENE

1.52 g of 2-methoxynaphthaldehyde (8.16 mmol), 0.4 g of ammonium acetate(5.19 mmol) and 20 cm³ of nitromethane (96%) are introduced into a50-cm³ two-necked round-bottomed flask equipped with a condenser. Thereaction mixture is heated to reflux for 1 h 30 min while stirring. Itbecomes yellow. The nitromethane is evaporated off in a rotaryevaporator and the residue is then taken up with dichloromethane.Hydrolysis of the ammonium acetate is carried out by pouring the abovemixture into water. The aqueous phase is washed twice with CH₂ Cl₂, theorganic phase once with water. The latter phase is dried with MgSO₄ andthe solvent is removed in a rotary evaporator. 1.77 g of yellow crystals(equivalent to 7.73 mmol of the expected product) are then obtained,corresponding to a 95% yield.

Melting point: 138.6°±0.4° C.

1H NMR (CDCl₃, 200 MHz) 4.04 ppm (3H (MeO), s) 8.82-8.76 ppm (1H(CHNO₂),d, J=13.35 H₃) 8.13-8.06 ppm (1H (naph-CH), d, J=13.42 H₃) 7.23-8.14 ppm(6H (arom), multipier consisting of 2 doublets of triplets:7.60-7.56-7.52 ppm, J=7.15 Hz, 7.41-7.37-7.34 ppm J=7.2 Hz, and of 4doublets: 8.14-8.09 ppm J=8.55 Hz, 7.94-7.90 ppm J=9.18 Hz, 7.78-7.74ppm J=8 Hz, 7.28-7.23 ppm J=9.7 Hz) Thin-layer chromatography: Rf=0.93(CH₂ Cl₂)

STAGE B': 2-(2-METHOXYNAPHTHYL)ETHYLAMINE

Under an inert atmosphere, 50 cm³ of anhydrous THF are introduced into a250-cm³ three-necked round-bottomed flask equipped with a condenser anda 100-cm³ dropping funnel, and 1.74 g (45.82 mmol) of LiAlH₄ are thenintroduced while cooling the flask in ice and stirring the reactionmedium. Under the same conditions, a mixture consisting of 2.05 g (8.94mmol) of compound obtained in the preceding stage and 75 cm³ of THF arethen added in the course of 1 h. After the introduction of reactants,the mixture is heated for approximately 24 h to a temperature of between30° and 40° C. Hydrolysis of the excess hydride is performed by coolingthe flask again with ice and adding 1.6 cm³ of water, 1.6 cm³ of 15%NaOH, 37 cm³ of ether and 4.7 cm³ of water. After filtration, themixture is dried with anhydrous sodium carbonate, concentrated in arotary evaporator and purified by chromatography on a silica column(eluents: ethyl acetate, Rf=0, then a mixture consisting of 15% ofmethanol, 10% of triethylamine and 75% of ethyl acetate, Rf=0.28). 1.42g (7.06 mmol) of 2-(2-methoxynaphthyl)ethylamine (orange-yellow viscousoil) are finally obtained, equivalent to a yield after purification of78.9%.

PREPARATIONS 2 TO 7:

Using the procedure described in Preparation 1, but replacing(2-methoxy-1-naphthyl)carbaldehyde in Stage A by:

(2,5,6-trimethoxy-1-naphthyl)carbaldehyde (Eur. J. Med. Chem. 1980, 19(3) pp 249-253),

PREPARATION 2: 2-(2,5,6-TRIMETHOXY-1-NAPHTHYL)ETHYLAMINE is obtained

6-hydroxy-2-methoxy-1-naphthyl)carbaldehyde (Eur. J. Med. Chem. 1983, 18(2), pp 169-174),

PREPARATION 3: 2-(6-HYDROXY-2-METHOXY-1-NAPHTHYL)ETHYLAMINE is obtained

(2,6-dipropoxy-1-naphthyl)carbaldehyde (J. Org. Chem. 1981, 46 (9), pp1832-1835),

PREPARATION 4: 2-(2,6-DIPROPOXY-1-NAPHTHYL)ETHYLAMINE is obtained

(5,6,7,8-tetrahydro-4-methyl-2-methoxy-1-naphthyl)carbaldehyde (Aust. J.Chem. 1981, 34 (2), pp 459-464),

PREPARATION 5:2-(5,6,7,8-TETRAHYDRO-4-METHYL-2-METHOXY-1NAPHTHYL)ETHYLAMINE isobtained

5-formyl-6-methoxy-1,4-benzodioxane (J. Heterocycl. Chem. 1989, 26 (1),pp 193-197),

PREPARATION 6: 2-(6-METHOXY-1,4-BENZODIOXAN-5-YL)ETHYLAMINE is obtained

7-formyl-6-methoxy-3-methylbenzofuran (Bull. Soc. Chim. Fr. 1975, 11-12,Pt. 2, pp 2763-2766),

PREPARATION 7: 2-(6-METHOXY-3-METHYLBENZOFURAN-7-YL)ETHYLAMINE isobtained.

PREPARATION 8: 2-(5-BROMO-2-METHOXYPHENYL)ETHYLAMINE

STAGE A: (5-BROMO-2-METHOXYPHENYL)METHANOL

30 cm³ of anhydrous tetrahydrofuran are placed in a 250-cm³ two-neckedflask. The flask is chilled and 2.66 g of lithium aluminum hydride areadded. 5.014 g of 5-bromo-2-methoxybenzaldehyde dissolved in 30 cm³ ofanhydrous tetrahydrofuran are added via a pressure-equalizing droppingfunnel (the assembly is under an argon atmosphere ). The dropping funnelis then rinsed with 10 cm³ of anhydrous tetrahydrofuran and the mixtureis left stirring vigorously at room temperature for 5 h. Hydrolysis iscarried out as follows:

addition of 2.7 cm³ of water, stirring of this mixture for 5 min,

addition of 2.7 cm³ of 15% sodium hydroxide solution, stirring for 5min,

then addition of 3 times 2.7 cm³ of water until a white mass isobtained.

Sodium sulfate is then incorporated in order to dry the mixture.

After filtration and concentration of the filtrate, a white solidweighing 4.4 g is obtained, analysis of which shows it to be the desiredalcohol.

¹ H NMR (CDCl₃, 200 MHz) 2.38 ppm (1H (OH), b.s.) 3.75 ppm (3H (CH₃ O),s.) 4.55 ppm (2H (CH₂ O), b.s.) 6.66 ppm (1H (aromatic), d. J=8.6 Hz)7.17-7.34 ppm (2H (aromatic), m.)

STAGE B: 5-BROMO-2-METHOXYBENZYL CHLORIDE

4.023 g of the compound obtained in Stage A are placed in a 100-cm³two-necked flask. The compound is dissolved in 28 cm³ of anhydroustoluene. The mixture is placed under argon. 1.5 cm³ of pyridine areintroduced with a syringe.

To this mixture which is stirred and chilled, 3.2 cm³ of thionylchloride diluted in 18 cm³ of anhydrous toluene are added via apressure-equalizing dropping funnel. After the addition, the ice bath isremoved. Reaction is allowed so proceed at room temperature for 18 h.The mixture is hydrolyzed by pouring it into ice. The resulting mixtureis left stirring vigorously for 45 min. The organic and aqueous phasesare separated. The organic phase is washed with water, then withsaturated aqueous sodium hydrogen carbonate solution and with saturatedaqueous sodium chloride solution. After drying over magnesium sulfateand concentration of the filtrate, an orange liquid is isolated andchromatographed on silica (eluent: ether/pentane, 20:80-40:60). Acolorless liquid of mass 4.17 g, which crystallizes in the cold state,is thereby collected.

¹ H NMR (CDCl₃, 200 MHz) 3.78 ppm (3H (CH₃ O), s.) 4.51 ppm (2H (CH₂Cl), s.) 6.69 ppm (1H (aromatic), d. J=8.6 Hz) 7.24-7.41 ppm (2H(arom.), m.)

STAGE C: 5-BROMO-1-CYANOMETHYL-2-METHOXYBENZENE

2.23 g of potassium cyanide and a small spatula of potassium iodide in35 cm³ of anhydrous dimethyl sulfoxide are added to 4.03 g of thecompound obtained above.

This mixture under argon is brought to 120°-140° C. for 5 h.

Treatment after the reaction yields a rust-colored liquid which ischromatographed on silica (eluent: ether/pentane: 30:70-100:0).

In order to obtain the pure compound, the first fraction isrecrystallized in the heated state in a hexane/ethyl acetate mixture.

1.35 g of yellow crystals of 5-bromo-1-cyanomethyl-2-methoxybenzene arethereby isolated, analysis of which confirms the purity.

Melting point: 60.7°±0.2° C.

¹ H NMR (CDCl₃, 200 MHz) 3.58 ppm (2H (CH₂ CN), s.) 3.78 ppm (3H (CH₃O), s.) 6.70 ppm (1H (aromatic), d. J=8.7 Hz) 7.34 ppm (1H (aromatic),d.d. J=2.3 Hz, J=8.7 Hz)

STAGE D: 2-(5-BROMO-2-METHOXYPHENYL)ETHYLAMINE

Using the procedure described in Stage D of Preparation 1, but replacing1-cyanomethyl-2-methoxynaphthalene by5-bromo-1-cyanomethyl-2-methoxybenzene obtained in the preceding stage,2-(5-bromo-2-methoxyphenyl)ethylamine is obtained.

PREPARATION 9: 1-METHYL-2-(2-METHOXY-1-NAPHTHYL)ETHYLAMINE

STAGE A: 2-NITRO-1-(2-METHOXY-1-NAPHTHYL)PROPENE

2.13 g (11.20×10⁻³ mol) of naphthaldehyde, 30 cm³ of nitroethane and0.54 g (7×10⁻³ mol) of ammonium acetate are introduced into around-bottomed flask. The mixture is stirred and heated to reflux for 2hours. The nitroethane is then evaporated off under reduced pressure,the residue is taken up with CH₂ Cl₂ and water is added to hydrolyze theacetate. After separation of the two phases, the organic phase is washedwith water, the aqueous phases with CH₂ Cl₂ (twice). The organic phaseis then dried over MgSO₄ and concentrated under reduced pressure. 2.59 g(10.64×10⁻³ mol) of the expected nitroethylenic compound (yellow solid)are then obtained, equivalent to a 95% yield.

Melting point: 72°±3° C.

¹ H NMR (200 MHz, CDCl₃) δ (ppm): Z compound: 2.1 (s, 3H, CH₃); 3.97 (s,3H, MeO); 7.23/7.96 (n, 6H, aromatic); 8.33 (s, 1H, ethylenic H) (68%) Ecompound: 2.52 (s, 3H, CH₃); 3.89 (s, 3H, MeO); 6.92 (s, 1H, ethylenicH); 7.23/7.96 (n, 6H, aromatic) (32%)

STAGE B: 1-METHYL-2-(2-METHOXY-1-NAPHTHYL)ETHYLAMINE

50 cm³ of anhydrous THF are introduced into a 250-cm³ three-necked flaskunder an inert atmosphere, the solvent is stirred and the flask iscooled with ice. 1.45 g (38.19×10⁻³ mol) of LiAlH₄ are introduced insmall portions, and a mixture consisting of 60 cm³ of anhydrous THF and2.09 g (8.59×10⁻³ mol) of the nitroethylenic compound is then introduceddropwise. The ice bath is then removed, and after the mixture isreturned to room temperature, it is heated to 40° C. for 24 h.Hydrolysis of the excess hydride is carried out as follows: the mixtureis cooled with ice, and 1.5 cm³ of water, 1.5 cm³ of 15% sodiumhydroxide, 30 cm³ of ether and 4.5 cm³ of water are added. The mixtureis filtered and the filtrate is then dried over MgSO₄ and evaporated todryness. The residue obtained is purified by chromatography on a silicacolumn (eluent: ethyl acetate, then 15:3:2 ethylacetate/methanol/triethylamine mixture). 1.09 g (5.06×10⁻³ mol) of theexpected amine are finally isolated, equivalent to a 59% yield.

PREPARATION 10: 2-(2-METHOXY-5-METHYLPHENYL)ETHYLAMINE

STAGE A: METHYL 2-METHOXY-5-METHYLBENZOATE

5.07 g (33.32×10⁻³ mol) of 5-methylsalicylic acid and 22.33 g(161.6×10⁻³ mol) of anhydrous potassium carbonate are introduced into a250-cm³ two-necked flask. 175 cm³ of anhydrous acetone are added underan inert atmosphere. The reaction mixture is stirred, 7.25 cm³(76.62×10⁻³ mol) of dimethyl sulfate are added with a syringe and themixture is brought to reflux for 6 h. Hydrolysis of the dimethyl sulfateis performed by adding 5 cm³ of water. After filtration and evaporationof the solvent, the residue is taken up with dichloromethane, dried overMgSO₄ and then evaporated to dryness. The crude product is purified bychromatography on a silica column (eluent: CH₂ Cl₂) to give 5.47 g(30.36×10⁻³ mol) of the expected ester, equivalent to a 91% yield.

Boiling point (12 mmHg): 128°-132° C.

STAGE B: (2-METHOXY-5-METHYLPHENYL)METHANOL

1.56 g (41.08×10⁻³ mol) of LiAlH₄ are introduced into a 500-cm³three-necked flask containing 100 cm³ of anhydrous THF and under aninert atmosphere, while cooling the flask with an ice bath. A mixtureconsisting of 4.99 g (27.69×10⁻³ mol) of the above ester and 150 cm³ ofanhydrous THF is then introduced dropwise in the course of 1 hour, theflask being maintained at 0° C.

After it has returned to room temperature, the reaction mixture isheated to reflux for 20 h. Hydrolysis of the excess hydride is performedby cooling the flask with ice and adding slowly 1.3 cm³ of water, then1.3 cm³ of 15% sodium hydroxide, 40 cm³ of ether and 5 cm³ of water.After filtration, drying of the filtrate with MgSO₄ and evaporationthereof to dryness, the residue is purified by vacuum distillation togive 3.68 g (24.18×10⁻³ mol) of the expected alcohol, equivalent to an87% yield.

Boiling point (12 mmHg): 130°-132° C.

STAGE C: 2-METHOXY-5-METHYLBENZYL CHLORIDE

3.23 g (21.22×10⁻³ mol) of benzyl alcohol and 50 cm³ of anhydroustoluene are introduced into a 100-cm³ three-necked flask. Under argon,while stirring and cooling the reaction mixture, 1.70 cm³ (21.10×10⁻³mol) of pyridine dried over potassium hydroxide are introduced, followedby 3.5 cm³ (47.98×10⁻³ mol) of thionyl chloride. A white precipitateforms and hydrogen chloride is evolved. After introduction of thereactants, reaction is allowed to proceed at room temperature forapproximately 24 h. The mixture is then poured into an ice bath andstirred for 1 h. The organic phase is recovered, washed with water,saturated sodium bicarbonate solution and saturated sodium chloridesolution and lastly dried over MgSO₄. After evaporation to dryness, theresidue is purified by vacuum distillation and 2.5 g (14.65×10⁻³ mol) ofthe expected chloride are obtained, equivalent to a 69% yield.

Boiling point (13 mmHg): 117°-120° C.

STAGE D: 1-CYANOMETHYL-2-METHOXY-5-METHYLBENZENE

2.44 g (14.30×10⁻³ mol) of the benzyl chloride obtained in the precedingstage and 50 cm³ of dimethyl sulfoxide (DMSO) are introduced into a250-cm³ three-necked flask. The mixture is stirred and, under an inertatmosphere, a spatula of potassium iodide and 1.85 g (28.41×10⁻³ mol) ofpotassium cyanide are added. Reaction is allowed to proceed at roomtemperature for 20 h. After evaporation of the DMSO under vacuum, theresidue is taken up with CH₂ Cl₂ and the KCN and KI are hydrolyzed byadding water. The aqueous phase is washed with dichloromethane, and thecombined organic phases with water. The latter phases are then driedover MgSO₄ and evaporated to dryness. The crude product obtained ispurified by distillation under reduced pressure, and 2.11 g (13.09×10⁻³mol) of the expected nitrile are obtained, equivalent to a 91% yield.

Boiling point (16 mmHg)=136°-140° C.

STAGE E: 2-(2-METHOXY-5-METHYLPHENYL)ETHYLAMINE

1.7 g (10.54×10⁻³ mol) of nitrile, 38 cm³ of 95.96% ethanol and 3.8 cm³of ammonia solution are introduced into a 100-cm³ three-necked flask.Under an inert atmosphere, a spatula-tip of Raney nickel is introduced.After the whole of the assembly has been placed under vacuum, a hydrogenatmosphere is established therein and the reaction medium is stirredvigorously. It is then heated to 40°-50° C. for approximately 48 h.After cooling, the mixture is filtered through Celite and the latter iswashed with ethanol. The filtrate is evaporated to dryness, the residueis taken up with ether and the mixture is evaporated again. The crudeproduct obtained is purified by converting the amine obtained to thehydrochloride. A greenish-yellow solid product is obtained, which has tobe recrystallized in an ethanol/ether mixture. 1.07 g (5.31×10⁻³ mol) ofwhite hydrochloride are then obtained.

Melting point: 170°±3° C.

Elemental analysis: C theo=59.55% C exp=59.39% H theo=7.99% H exp=7.85%N theo=6.94% H exp=6.78% Cl theo=17.58% Cl exp=17.54%

PREPARATION 11: 2-(5-ETHYL-2-METHOXYPHENYL)ETHYLAMINE

20 cm³ of anhydrous THF are introduced into a 50-cm³ three-necked flaskunder an inert atmosphere, and the solvent is stirred and cooled withice. 0.43 g (11.32×10⁻³ mol) of LiAlH₄ is then introduced in smallportions. 0.51 g (2.45×10⁻³ mol) of1-nitro-2-(5-ethyl-2-methoxyphenyl)ethylene, prepared according tosynthesis methods known to a person skilled in the art, is thenintroduced dropwise.

After the introduction, the reaction medium is heated to 40° C. for 18h. After cooling, the excess hydride is hydrolyzed by adding 0.5 cm³ ofwater, 0.5 cm³ of 15% NaOH, 15 cm³ of ether and 1.5 cm³ of water to themixture cooled with ice. After filtration, the filtrate is dried overMgSO₄ and evaporated to dryness, and the residue is purified bychromatography on a silica column (eluent: ethyl acetate, then ethylacetate/MeOH/Et₃ N, 15:3:2). The amine obtained is solubilized in CH₂Cl₂, and 2 equivalents (eq.) of ethereal hydrogen chloride are thenadded. After evaporation of the solvents, a beige precipitate isobtained, which has to be recrystallized in an ethanol/ether mixture.150 mg (6.95×10⁻³ mol) are finally obtained, equivalent to a final yieldof 28% of the hydrochloride of the expected amine.

Melting point: 173°±3° C.

EXAMPLE 1

N-[2-(2-METHOXY-1-NAPHTHYL)ETHYL]ACETAMIDE

0.3 g (1.2 mmol) of 2-(2-methoxy-1-naphthyl)ethylamine hydrochloride(Preparation 1) is placed in a 50-cm³ two-necked flask. 10 cm³ ofdistilled water are added until the crystals have dissolved, followed by0.1 g of sodium acetate (13 equivalents). 3 cm³ of acetic anhydride (25equivalents) are added to this mixture with stirring. The solutionbecomes milky, a slight evolution of heat takes place and the solutionthen becomes clear. After 25 min of reaction the mixture is extractedwith dichloromethane. The organic phases are washed with saturatedaqueous sodium hydrogen carbonate solution and then with water and driedover magnesium sulfate. The concentrated filtrate gives pale yellowcrystals, which are recrystallized directly in the heated state in ahexane/ethyl acetate mixture.

0.235 g of white crystals of N-[2-(2-methoxy-1-naphthyl)ethyl]acetamideis thereby obtained.

Yield: 76.8%

Melting point: 138.7° C.

¹ H NMR (CDCl₃, 200 MHz) 3.22-3.29 ppm (2H (CH₂ N), m.) 3.43-3.52 ppm(2H (CH₂ O), m.) 3.90 ppm (3H (CH₃ O), s.) 5.69 ppm (1H (NH), b.s.)7.19-7.31 ppm (2H (aromatic), m.) 7.39-7.47 ppm (1H (aromatic), m.)7.68-7.74 ppm (2H (aromatic), m.) 7.94 ppm (1H (atom.), d. J=8.6 Hz)

EXAMPLE 2

N-[2-(2-METHOXY-1-NAPHTHYL)ETHYL]PROPIONAMIDE

First method:

0.22 g of 2-(2-methoxy-1-naphthylethylamine) is placed in a 25-cm³two-necked flask. The compound is diluted with 5.3 cm³ of anhydrousdichloromethane (3 equivalents). After the mixture has been placed underargon and the flask has been chilled, 0.250 cm³ of triethylamine isadded to the mixture, followed by 0.160 cm³ of propanoyl chloride addedslowly (1 equivalent each). After 30 min of reaction at roomtemperature, subsequent treatment yields a brown liquid which ischromatographed on a silica column (eluent: CH₂ Cl₂ /methane, 0.2%). Theproduct isolated crystallizes at room temperature. It is recrystallizedby dissolution in the heated state in a hexane/ethyl acetate mixture.

0.193 g of beige crystals ofN-[2-(2-methoxy-1-naphthyl)ethyl]propionamide is thereby obtained.

Melting point: 100.2°±0.2° C.

¹ H NMR (CDCl₃, 200 MHz) 1.01 ppm (3H (CH₃), t. J=7.6 Hz) 2.05 ppm (2H(CH₂), q. J=7.6 Hz) 3.23-3.29 ppm (2H (CH₂), m.) 3.44-3.54 ppm (2H (CH₂N), m.) 3.90 ppm (3H (CH₃ O), s.) 5.70 ppm (1H (NH), b.s.) 7.24-7.47 ppm(3H (aromatic), m.) 7.68-7.73 ppm (2H (aromatic), m.) 7.95 ppm (1H(arom.), d. J=8.6 Hz) Elemental analysis (C₁₆ H₁₉ NO₂)

    ______________________________________                                                  calculated                                                                            found                                                       ______________________________________                                        C           74.68%    74.15%                                                  H           7.44%     7.38%                                                   N           5.44%     5.26%                                                   ______________________________________                                    

Second method:

1.40 g (6.96 mmol) of 2-(2-methoxynaphthyl)ethylamine, which issolubilized in 20 cm³ of anhydrous dichloromethane, are introduced intoa 100-cm³ two-necked flask under an inert atmosphere. The mixture iscooled with an ice bath and stirred, and 1.5 cm³ (10.4 mmol) oftriethylamine dried over potassium hydroxide and 0.7 cm³ (8.056 mmol) ofpropanoyl chloride are introduced. After the introduction of thereactants, the ice bath is removed and reaction is allowed to proceed atroom temperature for 30 min. Hydrolysis of the excess chloride iscarried out by pouring the reaction mixture into water. After extractionthree times with dichloromethane, the organic phase is dried overmagnesium sulfate. After evaporation of the solvent andrecrystallization of the solid obtained, in the heated state, in apentane/ethyl acetate mixture, 0.70 g (2.72 mmol) ofN-[2-(2-methoxy-1-naphthyl)ethyl]propionamide (white solid) is obtained,equivalent to a yield after purification of 39%. ##STR19##

EXAMPLE 3

N-[2-(2-METHOXY-1-NAPHTHYL)ETHYL]CYCLOPROPYLCARBOXAMIDE

Using the procedure described in Example 2, but withcyclopropanecarbonyl chloride instead of propanoyl chloride, thecompound of the title is obtained:

Melting point: 127.5°±0.2° C.

¹ H NMR (CDCl₃, 200 MHz) 0.56-0.65 ppm (2H (CH₂ (cyclopropyl)), m.)0.85-0.92 ppm (2H (CH₂ (cyclopropyl)), m.) 1.08-1.18 ppm (1H (CH(cyclopropyl)), m.) 3.23-3.30 ppm (2H (CH₂) m.) 3.44-3.54 ppm (2H (CH₂N) m.) 3.90 ppm (3H(CH₃ --O), s.) 5.86 ppm (1H(NH), b.s.)

EXAMPLE 4

N-[2-(2-METHOXY-1-NAPHTHYL)ETHYL]TRIFLUOROACETAMIDE

0.338 g of 2-(2-methoxy-1-naphthyl)ethylamine is placed in a 25-cm³two-necked flask. It is diluted with 5 cm³ of anhydrous dichloromethane(3 equivalents). After the flask has been placed under argon, 0.15 cm³of pyridine stored over potassium hydroxide (1.1 equivalents) is added,the flask is chilled and 0.24 cm³ of trifluoroacetic anhydride (1equivalent) is added slowly. The reaction lasts 30 minutes at roomtemperature. Treatment after the reaction yields 0.220 g of viscousyellow liquid which crystallizes at room temperature. It isrecrystallized by dissolution in the heated state in a hexane/ethylacetate mixture.

52 mg of white crystals corresponding to the compound of the title arethereby obtained:

Melting point: 87.4°±0.2° C.

¹ H NMR (CDCl₃, 200 MHz) 3.30-3.37 ppm (2H (CH₂), m.) 3.55-3.64 ppm (2H(CH₂ N), m.) 3.91 ppm (3H (CH₃ O), s.) 6.97 ppm (1H (NH), b.s.)7.18-7.49 ppm (3H (arom.), m.) 7.72-7.87 ppm (3H (arom.), m.)

¹⁹ F NMR (CDCl₃, 188.3 MHz) 75.99 ppm (CF₃, s.)

EXAMPLE 5

N-[2-(2-METHOXYNAPHTHYL)ETHYL]BUTYRAMIDE ##STR20##

0.45 g (2.23 mmol) of 2-(2-methoxy-1-naphthyl)ethylamine, which issolubilized in 20 cm³ of anhydrous dichloromethane, is introduced into a100-cm³ two-necked flask under an inert atmosphere. The mixture iscooled with an ice bath and stirred, and 0.47 cm³ (3.37 mmol) oftriethylamine dried over potassium hydroxide is introduced, followed by0.28 cm³ (2.69 mmol) of butyryl chloride. After the introduction of thereactants, the ice bath is removed and reaction is allowed to proceed atroom temperature for 30 min. Hydrolysis of the excess chloride iscarried out by pouring the reaction mixture into water. After extractionthree times with dichloromethane, the organic phase is dried overmagnesium sulfate. After evaporation of the solvent andrecrystallization of the solid obtained, in the heated state, in apentane/ethyl acetate mixture, 0.29 g (1.07 mmol) ofN-[2-(2-methexynaphthyl)ethyl]butyramide (white solid) is obtained,equivalent to a yield after purification of 48%.

Melting point: 76°±3° C.

Elemental analysis: C theo=75.24% C exp=75.14% H theo=7.80% H exp=7.84%N theo=5.16% N exp=5.16%

EXAMPLE 6

N-[2-(2-METHOXY-1-NAPHTHYL)ETHYL]PENTANAMIDE

0.59 g (2.93 mmol) of 2-(2-methoxy-1-naphthyl)ethylamine, which issolubilized in 20 cm³ of anhydrous dichloromethane, is introduced into a100-cm³ two-necked flask under an inert atmosphere. The mixture iscooled with an ice bath and stirred, and 0.61 cm³ (4.37 mmol) oftriethylamine dried over potassium hydroxide, is introduced, followed by0.42 cm³ (3.54 mmol) of valeryl chloride. After the introduction of thereactants, the ice bath is removed and reaction is allowed to proceed atroom temperature for 30 min. Hydrolysis of the excess chloride iscarried out by pouring the reaction mixture into water. After extractionthree times with dichloromethane, the organic phase is dried overmagnesium sulfate. After evaporation of the solvent andrecrystallization of the solid obtained, in the heated state, in apentane/ethyl acetate mixture, 0.39 g (1.37 mmol) ofN-[2-(2-methoxynaphthyl)ethyl]pentanamide (white solid) is obtained,equivalent to a yield after purification of 47%.

Melting point: 72°±3° C.

EXAMPLES 7 TO 12

Using the procedure described in Example 2, but replacing propanoylchloride by the appropriate acid chloride, the compounds of thefollowing examples are obtained:

EXAMPLE 7

N-[2-(2-METHOXY-1-NAPHTHYL)ETHYL]HEXANAMIDE

EXAMPLE 8

N-[2-(2-METHOXY-1-NAPHTHYL)ETHYL]HEPTANAMIDE

EXAMPLE 9

N-[2-(2-METHOXY-1-NAPTHYL)ETHYL]CROTONAMIDE

EXAMPLE 10

N-[2-(2-METHOXY-1-NAPHTHYL)ETHYL]CYCLOBUTYLCARBOXAMIDE

EXAMPLE 11

N-[2-(2-METHOXY-1-NAPHTHYL)ETHYL]-4-CHLOROBUTYRAMIDE

EXAMPLE 12

N-[2-(2-METHOXY-1-NAPHTHYL)ETHYL]CYCLOHEXYLCARBOXAMIDE

EXAMPLE 13

N-[2-(2,5,6-TRIMETHOXY-1-NAPHTHYL)ETHYL]ACETAMIDE

Using the procedure described in Example 1, but replacing2-(2-methoxy-1-naphthyl)ethylamine by2-(2,5,6trimethoxy-1-naphthyl)ethylamine (Preparation 2), the compoundof the title is obtained.

EXAMPLES 14 TO 18

Using the procedure described in Example 1, but replacing2-(2-methoxy-1-naphthyl) ethylamine successively by the compounds ofPreparations 3 to 7, the compounds of the following examples areobtained:

EXAMPLE 14

N-[2-(6-[HYDROXY-2-METHOXY-1-NAPHTHYL)ETHYL]ACETAMIDE

EXAMPLE 15

N-[2-(2,6-DIPROPOXY-1-NAPHTHYL)ETHYL]ACETAMIDE

EXAMPLE 16

N-[2 -(5,6,7,8-TETRAHYDRO-4-METHYL-2-METHOXY-1-NAPHTHYL)ETHYL]ACETAMIDE

EXAMPLE 17

N-[2-(6-METHOXY-1,4-BENZODIOXAN-5-YL)ETHYL]ACETAMIDE

EXAMPLE 18

N-[2-(6-METHOXY-3-METHYLBENZOFURAN-7-YL)ETHYL]ACETAMIDE

EXAMPLE 19

N-[2-(5-METHOXY-4-INDOLYL)ETHYL]ACETAMIDE

Using the procedure described in Example 1, but replacing2-(2-methoxy-1-naphthyl)ethylamine by 2-(5-methoxy-4-indolyl)ethylamine(Bull. Soc. Chim. Fr. 1973, (6) (Pt. 2), pp 2046-2057), the compound ofthe title is prepared.

EXAMPLES 20 TO 22

Using the procedure described in Examples 2 to 4, but replacing2-(2-methoxy-1-naphthyl)ethylamine by 2-(5-methoxy-4-indolyl)ethylamineand using the appropriate chlorides or anhydrides, the compounds of thefollowing examples are successively obtained:

EXAMPLE 20

N-[2-(5-METHOXY-4-INDOLYL)ETHYL]PROPIONAMIDE

EXAMPLE 21

N-[2-(5-METHOXY-4-INDOLYL)ETHYL]CYCLOPROPYLCARBOXAMIDE

EXAMPLE 22

N-(2-(5-METHOXY-4-INDOLYL)ETHYL]TRIFLUOROACETAMIDE

EXAMPLE 23

N-[2-(2-HYDROXY-5-NITROPHENYL)ETHYL]CYCLOPROPYLCARBOXAMIDE

Using the procedure described in Example 3, but replacing2-(2-methoxy-1-naphthyl)ethylamine by2-(2-hydroxy-5-nitrophenyl)ethylamine (Tetrahedron Letters 1990, vol 31,No. 9, pp 1275-1278), the compound of the title is obtained.

EXAMPLE 24

N-[2-(5-BROMO-2-METHOXYPBENYL)ETHYL]CYCLOPROPYLCARBOXAMIDE

Using the procedure described in Example 3, but replacing2-(2-methoxy-1-naphthyl)ethylamine by2-(5-bromo-2-methoxyphenyl)ethylamine (Preparation 8), the compound ofthe title is obtained.

EXAMPLES 25 TO 27

Using the procedure described in Example 24, but with the appropriateacyl chlorides, the compounds of the following examples are obtained:

EXAMPLE 25

N-[2-(5-BROMO-2-METHOXYPHENYL)ETHYL]CYCLOBUTYLCARBOXAMIDE

EXAMPLE 26

N-[2-(5-BROMO-2-METHOXYPHENYL)ETHYL]CYCLOHEXYLCARBOXAMIDE

EXAMPLE 27

N-[2-(5-BROMO-2-METHOXYPHENYL)ETHYL]CYCLOPENTYLPROPIONAMIDE

EXAMPLE 28

N-[2-(2-METHOXY-1-NAPHTHYL)-1-METHYLETHYL]ACETAMIDE

0.37 g (1.72×10⁻³ mol) of the amine obtained in Preparation 9 and 20 cm³of anhydrous dichloromethane are introduced under an inert atmosphereinto a 100-cm³ two-necked flask. The mixture is stirred and cooled, then0.32 cm³ (2.29×10⁻³ mol) of triethylamine dried over potassium hydroxideand lastly 0.13 cm³ (1.84×10⁻³ mol) of acetyl chloride are introduced.The ice is then removed and reaction is allowed to proceed at roomtemperature for 1/2 hour. Hydrolysis is carried out by pouring themixture into a stirred waterbath. After separation of the two phases,the aqueous phase is washed twice with CH₂ C₁₂ and the combined organicphases are dried over MgSO₄. After evaporation of the latter phasesdryness, the residue is purified by chromatography on a silica column(eluent: MeOH/CH₂ Cl₂, 2:98), and 0.4 g (1.55×10⁻³ mol) of whitecrystals of the expected acetamide is recovered, equivalent to a 90%yield.

Melting point: 151°±3° C.

EXAMPLES 29 TO 34

Using the procedure described in Example 28, but replacing acetylchloride by the appropriate acyl chloride or anhydride, the compounds ofthe following examples are obtained:

EXAMPLE 29

N-[2-(2-METHOXY-1-NAPHTHYL)-1-METHYLETHYL]PROPIONAMIDE

Melting point: 133°±3° C.

Elemental analysis: C theo=75.24% C exp=74.98% H theo=7.80% H exp=7.91%N theo=5 16% N exp=5.10%

EXAMPLE 30

N-[2-(2-METHOXY-1-NAPHTHYL)-1-METHYLETHYL]TRIFLUOROACETAMIDE

Melting point: 123°±3° C.

Elemental analysis: C theo=61.73% C exp=61.54% H theo=5.18% H exp=5.29%N theo=4.50% N exp=4.40%

EXAMPLE 31

N-[2-(2-METHOXY-1-NAPHTHYL)METHYLETHYL]CYCLOPROPYLCARBOXAMIDE

EXAMPLE 32

N-[2-(2-METHOXY-1-NAPHTHYL)-1-METHYLETHYL]BUTYRAMIDE

EXAMPLE 33

N-[2-(2-METHOXY-1-NAPHTHYL)-1-METHYLETHYL]PENTANAMIDE

EXAMPLE 34

N-[2-(2-METHOXY-1-NAPHTHYL)-1-METHYLETHYL]CYCLOBUTYLCARBOXAMIDE

EXAMPLE 35

N-[2-(2-METHOXY-5-METHYLPHENYL)ETHYL]ACETAMIDE

0.31 g (1.54×10⁻³ mol) of the hydrochloride of the amine obtained inPreparation 10, which is solubilized in approximately 15 cm³ of water,is introduced into a 100-cm³ two-necked flask. The mixture is stirred,1.6 g (19.51×10⁻³ mol) of sodium acetate are added and 3.6 cm³(38.15×10⁻³ mol) of acetic anhydride are then added with a syringe.Reaction is allowed to proceed at room temperature for 30 min. Theproduct formed is extracted from the aqueous phase three times with CH₂Cl₂. This organic phase is thereafter washed with saturated NaHCO₃solution and then with water, and lastly dried over MgSO₄ and evaporatedto dryness. The crude product obtained is purified by chromatography ona silica column (eluent: 5% MeOH, 95% CH₂ Cl₂), and 0.25 g (1.206×10⁻³mol) of the expected acetamide is then obtained, equivalent to a 79%yield.

Melting point: 76°±3° C.

Elemental analysis: C theo=69.54% C exp=69.36% N theo=6.76% N exp=6.72%H theo=8.27% H exp=8.40%

EXAMPLE 36

N-[2-(2-METHOXY-5-METHYLPHENYL)ETHYL]PROPIONAMIDE

Conversion to the free amine:

In an Erlenmeyer, 0.32 g (1.59×10⁻³ mol) of hydrochloride of the amineobtained in Preparation 10 is solubilized with water, and 2 equivalentsof 2 N sodium hydroxide, equivalent to 1.59 cm³, are added. The freeamine is extracted three times with CH₂ Cl₂ ; the organic phase iswashed with water, then dried over MgSO₄ and lastly evaporated todryness.

Acylation of the amine:

The amine obtained is introduced into a 1-cm³ three-necked flask andsolubilized in 20 cm³ of anhydrous dichloromethane. The mixture underargon is stirred and cooled with an ice bath. 0.33 cm³ (2.36×10⁻³ mol)of triethylamine is then introduced, followed by 0.17 cm³ (1.96×10⁻³mol) of propionyl chloride added slowly. Reaction is then allowed toproceed at room temperature for 30 min. Hydrolysis is performed bypouring the reaction mixture into water. The expected organic product isextracted three times with dichloromethane, and the combined organicphases are dried over MgSO₄ and then evaporated to dryness. The solidresidue obtained is purified by chromatography on a silica column(eluent: MeOH/CH₂ Cl₂, 5:95). 0.30 g (1.36×10⁻³ mol) of the expectedpropionamide (white solid) is then obtained, equivalent to an 85% yield.

Melting point: 70°±3° C.

Elemental analysis: C theo=70.56% C exp=70.32% H theo=8.65% H exp=8.79%N theo=6.33% N exp=6.24%

EXAMPLE 37

N-[2-(2-METHOXY-5-METHYLPHENYL)ETHYL]TRIFLUOROACETAMIDE

Conversion of the hydrochloride to the free amine is carried out in thesame manner as in Example 36, starting with 0.35 g (1.74×10⁻³ mol) ofhydrochloride. The amine obtained is introduced into a 100-cm³three-necked flask and solubilized with 20 cm³ of anhydrousdichloromethane. The mixture is stirred under an inert atmosphere andcooled with an ice bath, and 0.14 cm³ (1.73×10⁻³ mol) of pyridine driedover potassium hydroxide is introduced, followed by 0.29 cm³ (2.05×10⁻³mol) of trifluoroacetic anhydride. Reaction is then allowed to proceedat room temperature for 30 min. The excess anhydride is hydrolyzed bypouring the reaction mixture into stirred water, and then, afterseparation of the two phases, the expected organic product is extractedthree times with CH₂ Cl₂. The resulting organic phase is washed withsaturated NaHCO₃ solution and then with water, dried over MgSO₄ andevaporated to dryness. The residue obtained is purified bychromatography on a silica column (eluent: MeOH/CH₂ Cl₂, 2:98). 0.34 g(1.30×10⁻³ mol) of the expected amide is finally obtained, equivalent toa 75% yield.

Melting point: 77°±3° C.

Elemental analysis: C theo=55.17% C exp=55.27% H theo=5.40% H exo=5.46%N theo=5.36% N exp=5.30%

EXAMPLES 38 TO 40

Using the procedure described in Example 36, but replacing propionylchloride by the appropriate acyl chloride, the compounds of thefollowing examples are obtained:

EXAMPLE 38

N-[2-(2-METHOXY-5-METHYLPHENYL)ETHYL]BUTYRAMIDE

EXAMPLE 39

N-[2-(2-METHOXY-5-METHYLPHENYL)ETHYL]CYCLOPROPYLCARBOXAMIDE

EXAMPLE 40

N-[2-(2-METHOXY-5-METHYLPHENYL)ETHYL]HEXANAMIDE

EXAMPLE 41

N-[2-(5-ETHYL-2-METHOXYPHENYL)ETHYL]ACETAMIDE

68.8 mg (3.19×10⁻⁴ mol) of hydrochloride of the amine obtained inPreparation 11, which is solubilized with 10 cm³ of water, areintroduced into a 50-cm³ three-necked flask, followed by 0.4 g(4.88×10⁻³ mol) of sodium acetate. The reaction medium is stirred, 0.88cm³ (9.33×10⁻³ mol) of acetic anhydride is then added and reaction isallowed to proceed at room temperature for 40 min. The amide formed isextracted from the reaction medium three times with CH₂ Cl₂. Thisorganic phase is thereafter washed with saturated NaHCO₃ solution andthen with water, and lastly dried over MgSO₄ and evaporated to dryness.The solid residue obtained is purified by chromatography on a silicacolumn (eluent: MeOH/CH₂ Cl₂, 2:98), and 61.4 mg (2.78×10⁻⁴ mol) of theexpected amide are recovered, equivalent to an 87% yield.

Melting point: 82°±3° C.

Elemental analysis: C theo=70.56% C exp=70.36% H theo=8.65% H exp=8.72%N theo=6.33% N exp=6.23%

EXAMPLES 42 TO 44

Using the procedure described in Example 41, but replacing aceticanhydride by the appropriate acyl chloride or anhydride, the compoundsof the following examples are obtained:

EXAMPLE 42

N-[2-(5-ETHYL-2-METHOXYPHENYL)ETHYL]PROPIONAMIDE

EXAMPLE 43

N-[2-(5-ETHYL-2-METHOXYPHENYL)ETHYL]CYCLOPROPYLCARBOXAMIDE

EXAMPLE 44

N-[2-(5-ETHYL-2-METHOXYPHENYL)ETHYL]CYCLOBUTYLCARBOXAMIDE

PHARMACOLOGICAL STUDY

EXAMPLE A: STUDY OF ACUTE TOXICITY

Acute toxicity was assessed after oral administration to groups of 8mice (26±2 grams). The animals were observed at regular intervals duringthe first day and daily for two weeks following the treatment. The LD50,causing the death of 50% of the animals, was evaluated.

The LD₅₀ of the test products is greater than 1000 mg.kg⁻¹ the compoundsof the invention studied, indicating the absence of toxicity of thecompounds of the invention.

EXAMPLE B: STUDY OF BINDING TO MELATONIN RECEPTORS

Study of the affinity of the compounds of the invention for melatoninreceptors is carried out on chick brain membrane extracts according tothe method described by Yuan H. and Pang S. F. (Journal ofEndocrinology, (1991), 128, page 475-482).

PROTOCOL:

Dissection of chick brains.

The brains are dissected rapidly at 4° C. and the structures are frozenat -80° C. The frozen structures are then homogenized in a Polytron in10 volumes of buffer (Tris: 50 mM, pH: 7.4, at 25° C.).

After 2 centrifugations at 44,000 g for 25 minutes and at 4° C., thepellets are resuspended in 10 volumes of the same buffer. The quantityof protein is determined by the Folin-Lowry method in the presence ofsodium dodecyl sulfate (SDS). The proteins are then fractionated andfrozen at -80° C.

MEASUREMENT OF BINDING TO MELATONIN RECEPTORS

Each assay is carried out in 0.25 cm³ of buffer (50 nM Tris, pH 7.4) andcontains 0.15 mg of proteins prepared above, 0.05 nM 2-[¹²⁵I]iodomelatonin and the test compounds at variable concentrations.

Incubation lasts 60 min at 25° C., and the incubation medium is thenfiltered on a Brandel Cell Harvester® with GF/B filters (Whatman).

The filters are rinsed three times with 4 cm³ of buffer (50 mM Tris, pH7.4).

Non-specific binding is determined in the presence of 10⁻⁵ M melatonin.

The radioactivity is counted with a β counter

The assays are carried out in triplicate.

RESULTS

The compounds of the invention possess a very high selective affinityfor melatonin receptors, it being possible for this affinity to behigher than that of melatonin itself.

No such noteworthy affinity is encountered with compounds possessing ahydroxyl or alkoxy radical in their structure at the meta or paraposition with respect to the alkylamide chain on the benzene ring,instead of the ortho position as claimed for the compounds of theinvention.

EXAMPLE C: PHARMACEUTICAL COMPOSITION: TABLETS

Tablets containing a 5 mg dose ofN-[2-(2-methoxy-1-naphthyl)ethyl]trifluoroacetamide

N-[2-(2-Methoxy-1-naphthyl)ethyl]-trifluoroacetamide 5 g

Wheat starch 15 g

Corn starch 15 g

Lactose 15 g

Magnesium stearate 2 g

Silica 1 g

Hydropropylcellulose 2 g

We claim:
 1. A compound which is selected from those of formula (I):##STR21## in which: A represents a --CH₂ --CH₂ -- chain, unsubstitutedor substituted with lower alkyl,R₁ represents hydrogen or lower alkyl,R₂ represents hydrogen, halogen, or lower alkyl, R₃ and R₄, togetherwith the benzene ring which carries them, form a naphthalene ring-systemE₃ : on the understanding that the portion of the ring-system E₃ formedby R₃ and R₄ and the two carbon atoms of the benzene ring which carrythem is:unhydrogenated or partially hydrogenated, and unsubstituted orsubstituted with one or more radicals chosen from: halogen, hydroxyl,lower alkyl, lower alkoxy, lower alkoxycarbonyl, and trifluoromethyl, R₅represents hydrogen or lower alkyl, R₆ represents a group ##STR22## inwhich X represents oxygen and R₇ represents a radical chosen from:loweralkyl, unsubstituted or substituted with one or more radicals chosenfrom halogen, hydroxyl, and lower alkoxy, linear or branched alkenylhaving 2 to 7 carbon atoms, inclusive, unsubstituted or substituted withone or more radicals chosen from halogen, hydroxyl, and lower alkoxy,and --(CH₂)_(m) --E₄ in which m represents 0 or 1 to 4, inclusive, andE₄ represents a mono- or bicyclic cycloalkyl having 3 to 12 carbonatoms, inclusive, unsubstituted or substituted with one or more radicalschosen from halogen, and lower alkyl, its optical isomers, and additionsalts thereof with a pharmaceutically-acceptable acid or base when R₃ orR₄ represents a salifiable group, on the understanding that the terms"lower alkyl" and "lower alkoxy" denote linear or branched groups having1 to 6 carbon atoms, inclusive, and that the terms "cycloalkenyl" and"alkenyl" denote hydrocarbon groups containing one or more double bonds.2. A compound as claimed in claim 1 in which R₁ represents a methylradical.
 3. A compound as claimed in claim 1 in which R₃ and R₄,together with the benzene ring which carries them, form a naphthalene,on the understanding that the benzene ring formed by R₃, R₄ and the 2carbon atoms which carry them is unhydrogenated and unsubstituted orsubstituted with one or more radicals chosen from halogen, hydroxyl,lower alkyl, lower alkoxy, lower alkoxycarbonyl, and trifluoromethyl. 4.A compound as claimed in claim 1 in which R₁ represents a methyl radicaland R₃ and R₄, together with the benzene ring which carries them, form anaphthalene, on the understanding that the benzene ring formed by R₃ andR₄ and the 2 carbon atoms which carry them is unsubstituted orsubstituted with one or more radicals chosen from: halogen, hydroxyl,lower alkyl, lower alkoxy, lower alkoxycarbonyl, and trifluoromethyl. 5.A compound as claimed in claim 1 which isN-[2-(2-methoxy-1-naphthyl)ethyl]acetamide.
 6. A compound as claimed inclaim 1 which is N-[2-(2-methoxy-1-naphthyl)ethyl]propionamide.
 7. Acompound as claimed in claim 1 which isN-[2-(2-methoxy-1-naphthyl)ethyl]cyclopropylcarboxamide.
 8. A compoundas claimed in claim 1 which isN-[2-(2-methoxy-1-naphthyl)ethyl]trifluoroacetamide.
 9. A pharmaceuticalcomposition containing as active principle a compound as claimed inclaim 1, in combination with one or more pharmaceutically-acceptableexcipients.
 10. A method of treating a mammal afflicted with a sleepdisorder comprising the step of administering to the said mammal anamount of a compound as claimed in claim 1 which binds at melatoninreceptors and is effective in the treatment of said disorder.